Inhibition of the enzymes making up cell signalling cascades have been the subject of intense efforts. Among them, one of the most universally over regulated ones is the PI3K-Akt-mTor cascade.
The “mammalian target of rapamycin” (mTOR) is a member of the family of PIKK kinases. It appears as a non-conventional family of serine/threonine kinase with a high molecular weight, the sequences of which are similar to that of PI3K. In cancer, mTOR is frequently over activated thus validating this enzyme as a therapeutic target. Two alkaloids of natural origin are presently used as a clinical drug. These are temsirolimus and everolimus.
The “phosphatidyl-inositol 3-kinase” (PI3K), as for it, is an ubiquitous enzyme which phosphorylates the hydroxyl group located in position 3 of phosphatidyl-inositol 4,5 biphosphate (PIP2). This reaction, which generates phosphatidyl-inositol 3,4,5 triphosphate (PIP3), will subsequently trigger a cascade of reactions which will favour apoptosis, cell proliferation, angiogenesis or progression of the cell cycle. PI3K is a heterodimer consisting of a catalytic sub-unit p110 and of a regulatory sub-unit p85. There are four types of isoforms α, β, γ and δ for the sub-unit p110. However, each isoform of the catalytic sub-unit will have a more or less predominant role depending on certain types of pathologies. PI3K α will be involved in many cancers, while PI3K β seems to be only involved in specific cancers and also in thrombosis phenomena. The isoforms PI3K γ and PI3K δ are involved in immune responses i.e. inflammatory mechanisms and auto-immune diseases.